Pan-cancer analysis of heterogeneity of tumor mutational burden and genomic mutation under treatment pressure.

BACKGROUND: High tumor mutational burden (TMB) is one of the widely researched predictive biomarkers of immune checkpoint inhibitors and has been shown to be closely related with response to immunotherapy in multiple cancer types. However, for patients who have failed conventional therapy and are about to undergo immunotherapy, there is no consensus recommendation on the timing of tumor sampling for TMB analysis, and the effects of different therapies on TMB have not been clarified. This retrospective observational study aimed to investigate the heterogeneity of TMB and genomic mutation under the treatment pressure. PATIENTS AND METHODS: We retrospectively collected the available genomic and therapeutic information from 8051 samples across 15 tumor types (>50 samples/tumor) found in 30 published studies and investigated the distribution and heterogeneity of TMB under treatment across diverse cohorts. RESULTS: This integrated analysis has shown anticancer treatments increased TMB. Significant effects of treatment on TMB were more frequently observed in tumor types with lower treatment-naïve TMB, including breast, prostate, and pediatric cancers. For different cancer therapies, chemotherapy was prone to be correlated with an increased TMB in most cancer types. Meanwhile, the fraction of the TMB-high category of breast, prostate, and bladder cancers and glioma increased significantly after chemotherapy. Several actionable genes including ERS1 and NF1 in breast cancer, as well as some prognostic markers including TERT in bladder cancer and IDH1 in glioma, were significantly changed in post-chemotherapy tumors compared to treatment-naïve tumors. CONCLUSION: Our study reveals the heterogeneity of TMB under treatment across diverse cancer types and provides evidences that chemotherapy was associated with increases in TMB as well as the fraction of TMB-high category, suggesting that resampling tumor tissues for calculating post-chemotherapy TMB could be a better option for predicting the response to immunotherapy, especially for tumors with initially low TMB.

[Analysis of the efficacy and safety of bone disease treatment in patients with newly diagnosed multiple myeloma treated with denosumab or zoledronic acid].

Objective: This study investigated the efficacy and safety of denosumab (DENOS) versus zoledronic acid (ZOL) in the bone disease treatment of newly diagnosed multiple myeloma. Methods: The clinical data of 80 patients with myeloma bone disease (MBD) at the Fifth Medical Center of PLA General Hospital between March 1, 2021 and June 30, 2023 were retrospectively reviewed. Eighteen patients with severe renal impairment (SRI, endogenous creatinine clearance rate<30 ml/min) were treated with DENOS, and 62 non-SRI patients were divided into DENOS (30 patients) and ZOL group (32 patients) . Results: Hypocalcemia was observed in 26 (33%) patients, and 22 patients developed hypocalcemia during the first treatment course. The incidence of hypocalcemia in the non-SRI patients of DENOS group was higher than that in the ZOL group [20% (6/30) vs 13% (4/32), P=0.028]. The incidence of hypocalcemia in SRI was 89% (16/18). Multivariate logistic regression analysis revealed that endogenous creatinine clearance rate<30 ml/min was significantly associated with hypocalcemia after DENOS administration (P<0.001). After 1 month of antiresorptive (AR) drug application, the decrease in the serum ß-C-terminal cross-linked carboxy-telopeptide of collagen type I concentrations of SRI and non-SRI patients in the DENOS group were significantly higher than that in the ZOL group (68% vs 59% vs 27%, P<0.001). The increase in serum procollagen type Ⅰ N-terminal propeptide concentrations of patients with or without SRI in the DENOS group were significantly higher than that in the ZOL group (34% vs 20% vs 11%, P<0.05). The level of intact parathyroid hormone in each group increased after AR drug treatment. None of the patients developed osteonecrosis of the jaw and renal adverse events, and no statistically significant differences in the overall response rate, complete remission and stringent complete remission rates were found among the groups (P>0.05), and the median PFS and OS time were not reached (P>0.05) . Conclusions: In the treatment of MBD, DENOS minimizes nephrotoxicity and has strong AR effect. Hypocalcemia is a common adverse event but is usually mild or moderate and manageable.

[Effectiveness and safety of multimodal analgesia in open gastrostomy in patients with end-stage head and neck cancer].

Objective: To investigate the effectiveness and safety of multimodal analgesia in patients with end-stage head and neck cancer in open gastrostomy surgery. Methods: This was a randomized controlled trial. From June to December 2023, 50 patients with end-stage head and neck cancer who underwent elective open gastrostomy surgery in Beijing Tongren Hospital Affiliated to Capital Medical University were prospectively selected. The patients were divided into multimodal analgesia group and local anesthesia group using the random number table method according to different anesthesia methods, with 25 cases in each group. In multimodal analgesia group, a multimodal analgesia regimen was adopted: ultrasound-guided abdominal wall nerve block (rectus sheath block and transverse abdominis plane block)+intravenous injection of oxycodone+intravenous injection of flurbiprofen axetil and dexamethasone. In local anesthesia group, local infiltration anesthesia with ropivacaine was adopted. The main outcome measure was the incidence of intraoperative pain numeric rating scale (NRS) score>3 points in the two groups. The secondary observation indicators included NRS score and hemodynamic indexes [mean arterial pressure (MAP) and heart rate (HR)] at various time points during surgery [before anesthesia (T0), at the time of incision (T1), 10 minutes after surgery (T2), during gastric body traction (T3), and at the end of surgery (T4)], incidence of adverse reactions, postoperative patient satisfaction score, as well as the NRS scores at rest and activity (coughing) within 24 hours after surgery. Results: The multimodal analgesia group included 21 males and 4 females, aged (61.4±9.9) years. There were 19 males and 6 females in the local anesthesia group, aged (58.6±10.8) years. The incidence of intraoperative NRS score>3 points and the incidence of salvage analgesia in the multimodal analgesia group were both 12.0% (3/25), which were lower than 60.0% (15/25) in the local anesthesia group, and the differences were statistically significant (all P<0.001); The NRS score [M (Q1, Q3)] at T3 in the multimodal analgesia group was 2 (2, 3) points, which were lower than 5 (3, 6) points in the local anesthesia group (P<0.05). There were smaller variabilities in MAP and HR in the multimodal analgesia group than those in the local anesthesia group (all P<0.05). The incidence of intraoperative tachycardia, surgical traction reaction, and nausea in the multimodal analgesia group was lower than that in the local anesthesia group (all P<0.05). The postoperative satisfaction score of patients in the multimodal analgesia group was (9.25±0.71) points, which were higher than (7.33±0.87) points in the local anesthesia group (P<0.001). NRS score during postoperative activity within 24 hours in the multimodal analgesia group were (2.36±0.75) points, which were lower than (3.03±0.81) points of the local anesthesia group (P=0.005). No adverse reactions such as urinary retention, nausea, vomiting and dizziness occurred in both groups. Conclusion: Compared with local anesthesia, the multimodal analgesic strategy could provide better analgesic effect and longer duration, better hemodynamic stability, and fewer intraoperative adverse reactions in patients with end-stage head and neck cancer undergoing open gastrostomy.

Comparative study on the magnetic properties of Fe-substituted Co2Sn1-xFexO4 spinel oxides and its exchange bias effect.

A series of Fe-substituted Co2Sn1-xFexO4 (0 ≤ x ≤ 0.4) inverse spinel's oxides was synthesized using the solid-state reaction method. X-ray analysis reveals a single-phase cubic structure with the space group Fd3m. The transition temperature is shown to increase with a higher Fe concentration in the Co2Sn1-xFexO4 spinel oxide. The ac susceptibility at different frequencies also confirms a spin-glassy state at lower temperatures. The sample with Fe substitution (x = 0.2) exhibits a significant exchange bias effect when subjected to a constant temperature of ~10 K. The susceptibility at high temperatures, as calculated using Curie-Wise fitting, suggests that the system undergoes a shift from antiferromagnetic exchange (x < 0.2) to ferromagnetic exchange (x > 0.2).

Working Through It: Lifetime Experiences of Employment Discrimination Among Older Black Americans and Implications for Labor Force Participation, Job Dissatisfaction, and Mental Health in Older Adulthood.

OBJECTIVES: To examine lifetime experiences of employment discrimination and their association with Black older adults' employment status and well-being. METHODS: We use data from the Health and Retirement Study's leave-behind questionnaire to characterize lifetime experiences of being unfairly fired, not hired, or not promoted among Black older adults (N = 2948) and test associations with labor force status at age 62, job satisfaction among those working, and depressive symptoms. RESULTS: Employment discrimination was commonly reported by Black older adults, especially among men and those with college educations. Employment discrimination was not associated with employment status at age 62 but was associated with job dissatisfaction (OR = 2.00, p = .001) and depressive symptoms (Beta = 0.34, p < .001). DISCUSSION: Findings suggest a negative association between employment discrimination at any point in the life course and Black older adults' well-being. Employment discrimination is an obstacle to healthy aging, yet improved discrimination survey items are needed to fully capture its impact on Black Americans.

Considerations for the use of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) in cross-country comparisons of cognitive aging and dementia.

INTRODUCTION: Informant reports are a critical component of dementia diagnoses, but the comparability of informant reports across countries is not well understood. METHODS: We compared the performance of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) using population-representative surveys in the United States (N = 3183), England (N = 1050), and India (N = 4047). RESULTS: Analyses of regression splines and comparisons of model fit showed strong associations between IQCODE and objective cognition at low cognitive functioning in the United States and England; in India, the association was weaker but consistent over the range of cognition. Associations between IQCODE score and informant generation (analysis of variance [ANOVA] p = 0.001), caregiver status (p < 0.001), and years known by the informant (p = 0.015) were different across countries after adjusting for objective cognition. DISCUSSION: In India, the IQCODE was less sensitive to impairments at the lowest levels of cognitive functioning. Country-specific adjustments to IQCODE scoring based on informant characteristics may improve cross-national comparisons. HIGHLIGHTS: Associations between IQCODE and cognitive testing were similar in the United States and England but differed in India. In India, the IQCODE may be less sensitive to impairments among those with low cognition and no education. Informant characteristics may differentially impact informant reports of decline across countries. Adjustments or culturally sensitive adaptations may improve cross-national comparability.

[Esthetic analysis of upper lip morphology variation after the cross-arch fixed restoration of maxillary implant-supported prostheses via radiographic methods].

Objective: To measure and analyze upper lip morphology variation before and after the cross-arch fixed restoration of the maxillary implant-supported prostheses using cone- beam CT (CBCT) to provide an esthetic objective reference for maxillary edentulous patients. Methods: There were 32 maxillary edentulous patients selected in the Department of Dental Implantology, The Affiliated Stomatological Hospital of Nanjing Medical University from January 2010 to December 2023. The CBCT data of patients with maxillary full-arch implant-supported fixed prostheses were retrospectively collected before implantation (T0), at the time of radio-guide insertion (T1), and after final repair (T2). The length and thickness of the upper lip were measured and analyzed at each time point, and the correlation between the upper lip contour data and facial esthetic parameters was analyzed. Results: After the final prosthodontic treatment, the length of the upper lip was significantly increased from (21.72±2.84) mm to (24.98±2.93) mm (t=-8.13, P<0.001) compared with that before implant treatment. The widths of the middle and vermilion of the upper lip (Sm-Hm/Ls-UP), were reduced from (13.24±1.41), (12.81±1.67) mm to (11.36±1.67), (10.21±1.69) mm, with significant differences (t=7.79, P<0001; t=9.37, P<0.001). The lower face height (Sn-Gn) was increased from (54.52±4.95) mm to (58.70±4.42) mm, with significant differences (t=-11.05, P<0.001). However, the nasolabial angle reduced significantly from 95.35°± 7.70°to 90.53°±7.28°(t=7.68, P<0.001). The width of the middle of the upper lip with a radiation guide was (10.94±1.24) mm, and it increased significantly compared with that after the final prosthesis treatment (t=-0.76, P<0.05). The proportion of straight upper lip profiles accounted for 59% (19/32), and the proportion of concave upper lip profiles accounted for 41% (13/32) after the final prosthesis treatment. In addition, the results of correlation analysis showed that the nasolabial angle variation was weak and negatively correlated with residual bone height (r=-0.37, P=0.490). Conclusions: After the treatment of the maxillary full-arch implant-supported fixed prosthesis, the length of the upper lip increases, and the thickness of the upper lip becomes significantly thin. The maxillary full-arch implant-supported fixed prostheses support upper lips to improve the patients' side appearances.

The association between incarceration and housing insecurity and advanced immune age during late life.

Emerging evidence suggests that psychosocial stress ages the immune system. Accordingly, immune aging may be an important potential mechanism linking psychosocial stress to aging-related decline and disease. Incarceration and housing insecurity represent severe and complex experiences of a multitude of psychosocial stressors, including discrimination, violence, and poverty. In this study, we investigated the association between incarceration and/or housing insecurity and advanced immune age in adults aged 55 and older. Our sample was derived from the Health and Retirement Survey (HRS), with n = 7003 individuals with valid housing insecurity data and n = 7523 with valid incarceration data. From 2016 Venous Blood Study data, we assessed immune aging using a comprehensive set of immune markers including inflammatory markers (IL-6, CRP, s-TNFR1), markers of viral control (CMV IgG antibodies), and ratios of T cell phenotypes (CD8+:CD4+, CD+ Memory: Naïve, CD4+ Memory: Naïve, CD8+ Memory: Naïve ratios). We found that both incarceration and housing insecurity were strongly associated with more advanced immune aging as indicated by increased inflammation, reduced viral control, and reduction in naïve T cells relative to memory T cells. Given that those who experienced incarceration, housing insecurity, and/or are racialized minorities were less likely to be included in this study, our results likely underestimated these associations. Despite these limitations, our study provided strong evidence that experiencing incarceration and/or housing insecurity may accelerate the aging of the immune system.

Protective effect of modified Huangqi Chifeng decoction on immunoglobulin A nephropathy through toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-kappa B signaling pathway.

OBJECTIVE: To examine the nephroprotective mechanism of modified Huangqi Chifeng decoction (, MHCD) in immunoglobulin A nephropathy (IgAN) rats. METHODS: To establish the IgAN rat model, the bovine serum albumin, lipopolysaccharide, and carbon tetrachloride 4 method was employed. The rats were then randomly assigned to the control, model, telmisartan, and high-, medium-, and low-dose MHCD groups, and were administered the respective treatments via intragastric administration for 8 weeks. The levels of 24-h urinary protein, serum creatinine (CRE), and blood urea nitrogen (BUN) were measured in each group. Pathological alterations were detected. IgA deposition was visualized through the use of immunofluorescence staining. The ultrastructure of the kidney was observed using a transmission electron microscope. The expression levels of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-ß1 (TGF-ß1) were examined by immunohistochemistry and quantitative polymerase chain reaction. Levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB) P65, were examined by immunohistochemistry, Western blotting, and quantitative polymerase chain reaction. RESULTS: The 24-h urine protein level in each group increased significantly at week 6, and worsen from then on. But this process can be reversed by treatments of telmisartan, and high-, medium-, and low-dose of MHCD, and these treatments did not affect renal function. Telmisartan, and high-, and medium-dose of MHCD reduced IgA deposition. Renal histopathology demonstrated the protective effect of high-, medium-, and low-dose of MHCD against kidney injury. The expression levels of MCP-1, IL-6, and TGF-ß1 in kidney tissues were downregulated by low, medium and high doses of MHCD treatment. Additionally, treatment of low, medium and high doses of MHCD decreased the protein and mRNA levels of TLR4, MyD88, and NF-κB. CONCLUSIONS: MHCD exerted nephroprotective effects on IgAN rats, and MHCD regulated the expressions of key targets in TLR4/MyD88/NF-κB signaling pathway, thereby alleviating renal inflammation by inhibiting MCP-1, IL-6 expressions, and ameliorating renal fibrosis by inhibiting TGF-ß1 expression.

Real-World Use of Oral and Subcutaneous Semaglutide in Routine Clinical Practice in the UK: A Single-Centre, Retrospective Observational Study.

INTRODUCTION: Semaglutide, the only glucagon-like peptide-1 receptor agonist (GLP-1 RA) available in subcutaneous and oral formulation for treatment of type 2 diabetes (T2D), has demonstrated clinically significant improvements in glycaemic control and weight in clinical trials. This study aimed to gain insights into the use of both formulations and evaluate their clinical effectiveness in a secondary care clinic in Wales. METHODS: This was a retrospective observational analysis of adults with T2D initiated on oral or subcutaneous semaglutide. Changes from baseline in glycated haemoglobin (HbA1c), weight and other metabolic parameters were evaluated. RESULTS: At baseline, participants (n = 103) had a mean age of 57.3 years, mean HbA1c of 79.1 mmol/mol (9.38%), mean weight of 111.8 kg and body mass index (BMI) of 39.6 kg/m2 (no statistically significant differences between oral and subcutaneous groups). At 6-month follow-up, statistically significant improvements in HbA1c (- 19.3 mmol/mol [- 1.77%] and - 20.8 mmol/mol [- 1.90%]), body weight (- 9.0 kg and - 7.2 kg), and BMI (- 3.3 kg/m2 and - 2.5 kg/m2) were observed for oral and subcutaneous semaglutide, respectively. No statistically significant differences between the formulations were observed, and safety profiles were comparable. CONCLUSIONS: Both formulations of semaglutide provided clinically and statistically significant reductions in HbA1c and weight in real-world practice. Oral GLP-1 RA may offer a practical and effective option for the management of T2D.

Development of a real-time impedance matching system for ion cyclotron resonance heating in experimental advanced superconducting tokamak.

To achieve stable operation of an ion cyclotron resonance heating (ICRH) system in the Experimental Advanced Superconducting Tokamak (EAST), a real-time impedance matching system needs to be established to respond to antenna load variation during long pulse discharges. A new impedance matching method based on capacitors was proposed in this study. By considering the reflected voltage of the transmission line as the feedback parameter, the real-time impedance-matching system can quickly control the motors based on a programmable logic controller to determine the minimum reflection voltage. A real-time impedance matching system was successfully used on the test platform in the laboratory and on the ICRH system in EAST. A significant result is that we can match the variable impedance within 1 s by suitably adjusting the motor controller to ensure high-power and long-pulse operation of the ICRH system to satisfy the requirements of the EAST experiment.

Educational Attainment and Later-Life Cognitive Function in High- and Middle-Income Countries: Evidence From the Harmonized Cognitive Assessment Protocol.

OBJECTIVES: Identifying social policies that can promote cognitive health is crucial for reducing the global burden of dementia. We evaluated the importance of educational attainment for later-life cognitive function in various social and geographic settings. METHODS: Using harmonized data for individuals aged ≥65 years from the United States Health and Retirement Study (HRS) and its international partner studies in England, Mexico, China, and India, and each study's respective Harmonized Cognitive Assessment Protocol (HCAP), we conducted a cross-national comparative study to examine the role of educational attainment in later-life cognitive function across countries (n = 14,980, 2016-2019). We used multivariable-adjusted regression to estimate associations between educational attainment and harmonized global cognitive function scores. RESULTS: In Mexico, China, and India, the general cognitive function scores on average are approximately one standard deviation of the HRS-HCAP cognitive function score distribution lower compared to the United States and England, paralleling patterns of educational attainment across countries. In all countries, higher educational attainment was associated with progressively higher later-life cognitive function scores. Population-level differences in educational attainment explained about 50%-90% of the observed differences in cognitive function scores across countries. DISCUSSION: The relationship between education and later-life cognitive function across social and geographic contexts underscores the crucial role of education to promote cognitive health and reduce dementia risk. Continual improvement of educational attainment in low- and middle-income settings may yield a significant pay-off in later-life cognitive health.

Design and analysis of radio frequency window for the China Fusion Engineering Test Reactor ion cyclotron range of frequency heating system.

The Ion Cyclotron Range of Frequency (ICRF) heating system of the China Fusion Engineering Test Reactor (CFETR) is intended to provide plasma heating with a minimum power output of 20 MW, which demands the Radio Frequency (RF) window to possess a higher performance requirement. This paper presents the design of an RF window for the CFETR ICRF heating system and focuses primarily on the design and confirmation of its electromagnetic performance. The RF window can be effectively matched in the operating frequency range and has an S11 of under -59 dB. The geometry of the cone type ceramics was optimized to reduce the surface tangential electric field distribution. An analysis of the electric field distribution of the RF window at 50 kV indicates that the pressure side was below 2.3 kV/mm and the vacuum side was below 1.3 kV/mm. Furthermore, a transmission line test bench with an open-terminated setup was constructed to conduct withstand voltage tests on the mockup, and the results showed that the mockup could withstand 62 kV for 2 s and 47 kV for 120 s.

Claudin-10 Decrease in the Submandibular Gland Contributes to Xerostomia.

Tight junction proteins play a crucial role in paracellular transport in salivary gland epithelia. It is clear that severe xerostomia in patients with HELIX syndrome is caused by mutations in the claudin-10 gene. However, little is known about the expression pattern and role of claudin-10 in saliva secretion in physical and disease conditions. In the present study, we found that only claudin-10b transcript was expressed in human and mouse submandibular gland (SMG) tissues, and claudin-10 protein was dominantly distributed at the apicolateral membranes of acini in human, rat, and mouse SMGs. Overexpression of claudin-10 significantly reduced transepithelial electrical resistance and increased paracellular transport of dextran and Na+ in SMG-C6 cells. In C57BL/6 mice, pilocarpine stimulation promoted secretion and cation concentration in saliva in a dose-dependent increase. Assembly of claudin-10 to the most apicolateral portions in acini of SMGs was observed in the lower pilocarpine (1 mg/kg)-treated group, and this phenomenon was much obvious in the higher pilocarpine (10 mg/kg)-treated group. Furthermore, 7-, 14-, and 21-wk-old nonobese diabetic (NOD) and BALB/c mice were used to mimic the progression of hyposalivation in Sjögren syndrome. Intensity of claudin-10 protein was obviously lower in SMGs of 14- and 21-wk-old NOD mice compared with that of age-matched BALB/c mice. In the cultured mouse SMG tissues, interferon-γ (IFN-γ) downregulated claudin-10 expression. In claudin-10-overexpressed SMG-C6 cells, paracellular permeability was decreased. Furthermore, IFN-γ stimulation increased p-STAT1 level, whereas pretreatment with JAK/STAT1 antagonist significantly alleviated the IFN-γ-induced claudin-10 downregulation. These results indicate that claudin-10 functions as a pore-forming component in acinar epithelia of SMGs, assembly of claudin-10 is required for saliva secretion, and downregulation of claudin-10 induces hyposecretion. These findings may provide new clues to novel therapeutic targets on hyposalivation.

Lipoprotein(a) is associated with recurrent cardiovascular events in patients with coronary artery disease and prediabetes or diabetes.

PURPOSE: Elevated lipoprotein(a) [Lp(a)] and diabetes mellitus (DM) are both associated with adverse events in high-risk patients with established coronary artery disease (CAD). Currently, the association between Lp(a) levels and recurrent cardiovascular (CV) events (CVEs) remained undetermined in patients with different glucose status. Therefore, this study aimed to investigate the prognostic significance of Lp(a) levels for recurrent CVEs in high-risk CAD patients who suffered from first CVEs according to different glycemic metabolism. METHODS: We recruited 5257 consecutive patients with prior CVEs and followed up for recurrent CVEs, including CV death, non-fatal myocardial infarction (MI), and non-fatal stroke. Patients were assigned to low, medium, and high groups according to Lp(a) levels and further stratified by glucose status. RESULTS: During a median 37-month follow-up, 225 (4.28%) recurrent CVEs occurred. High Lp(a) was independently associated with recurrent CVEs [adjusted Hazard Ratio (HR), 1.57; 95% confidence interval (CI) 1.12-2.19; P = 0.008]. When participants were classified according to Lp(a) levels and glycemic status, high Lp(a) levels were associated with an increased risk of recurrent CVEs in pre-DM (adjusted HR, 2.96; 95% CI 1.24-7.05; P = 0.014). Meanwhile, medium and high Lp(a) levels were both associated with an increased risk for recurrent CVEs in DM (adjusted HR, 3.09; 95% CI 1.30-7.34; P = 0.010 and adjusted HR, 3.13, 95% CI 1.30-7.53; P = 0.011, respectively). CONCLUSIONS: This study demonstrated that elevated Lp(a) levels were associated with an increased recurrent CVE risk in patients with CAD, particularly among those with pre-DM and DM, indicating that Lp(a) may provide incremental value in risk stratification in this population.

Time Path of Weight Status Before and After Incident Dementia.

Objectives: Identifying whether obesity is a risk factor for dementia is complicated by the possibility of weight change as dementia evolves. This article investigates an extended time path of body mass index (BMI) before and after incident dementia in a nationally representative sample. Methods: Using the Health and Retirement Study (2000-2016), we examine (1) the longitudinal relationship between BMI and incident dementia and (2) heterogeneity in the BMI trajectory by initial BMI level. Results: Weight loss begins at least one decade before incident dementia, then accelerates in the years immediately preceding dementia onset and continues after incident dementia. Those with higher levels of BMI at baseline experienced a much greater decline relative to those with a normal weight. Discussion: Our results help explain the contradicting findings in the literature regarding the relationship between obesity and dementia and highlight the need for using extended longitudinal data to understand dementia risk.

[Emodin alleviates joint inflammation and bone erosion in rats with collagen-induced arthritis by inhibiting ferroptosis and degrading matrix metalloproteinases].

OBJECTIVE: To investigate the osteoprotective mechanism of emodin in light of the ferroptosis signaling pathway in a rat model of rheumatoid arthritis. METHODS: SD rat models of collagen-induced arthritis (CIA) were treated with methotrexate or low or high doses of emodin, and the changes in arthritis scores and toe volume were recorded. model of CIA rats. Malondialdehyde (MDA) content in the joint cartilage was determined, and ankle joint tissue pathologies were observed using caffein solid green staining and hematoxylin-spermine red staining. MMP3 and MMP13 expressions in the ankle joint tissues were detected using immunohistochemistry, and Western blotting was used to detect the protein expressions of ACSL4, SLC7A11, GPX4, and FTH1. RESULTS: Compared with the normal control rats, the CIA rats showed significantly increased arthritis score index with obvious toe swelling (P<0.05), rough cartilage surface, and loss and irregular aligment of chondrocytes. The rat models also showed significantly increased MDA and ACSL4 contents, lowered SLC7A11, GPX4, and FTH1 contents (P<0.05), and decreased expressions of MMP3 and MMP13 in the ankle joint (P<0.05). The rat models treated with either methotrexate or emodin (40 and 80 mg/kg) had significantly reduced arthritis score index and toe swelling with smooth cartilage surface and neat arrangement of the chondrocytes. The treatments with methotrexate and emodin both decreased the contents of MDA and ACSL4 and increased the contents of SLC7A11, GPX4, and FTH1 in the joint tissues (P<0.05). CONCLUSION: Emodin can effectively control joint inflammation and improve joint bone erosion in CIA rats possibly by inhibiting the ferroptosis signaling pathways and reducing the expressions of MMP3 and MMP13.

Proton and molecular permeation through the basal plane of monolayer graphene oxide.

Two-dimensional (2D) materials offer a prospect of membranes that combine negligible gas permeability with high proton conductivity and could outperform the existing proton exchange membranes used in various applications including fuel cells. Graphene oxide (GO), a well-known 2D material, facilitates rapid proton transport along its basal plane but proton conductivity across it remains unknown. It is also often presumed that individual GO monolayers contain a large density of nanoscale pinholes that lead to considerable gas leakage across the GO basal plane. Here we show that relatively large, micrometer-scale areas of monolayer GO are impermeable to gases, including helium, while exhibiting proton conductivity through the basal plane which is nearly two orders of magnitude higher than that of graphene. These findings provide insights into the key properties of GO and demonstrate that chemical functionalization of 2D crystals can be utilized to enhance their proton transparency without compromising gas impermeability.

[Selection strategy of pedicled axial flaps for repairing high-voltage electric burn wounds in foot and ankle].

Objective: To explore the selection strategy of pedicled axial flaps for repairing high-voltage electric burn wounds in foot and ankle. Methods: The retrospective observational research method was used. From January 2017 to December 2022, 16 patients with skin and soft tissue defects in foot and ankle after high-voltage electric burns were treated in General Hospital of Eastern Theater Command, including 11 cases of unilateral defect and 5 cases of bilateral defect. All patients were male, aged from 25 to 75 years. After thorough debridement, the area of the defect to be repaired with the flap was 5.0 cm×4.0 cm to 12.0 cm×8.0 cm. Before operation, the color Doppler ultrasound, computed tomography angiography, or digital subtraction angiography was used to fully evaluate the degree of vascular injury in the affected limb and to identify the distribution and traffic anastomosis of vascular network. Pedicled axial flaps with reliable blood supply were used to repair the wounds as soon as possible, and the area of flaps ranged from 3.0 cm×2.0 cm to 13.0 cm×8.0 cm. The wound in the donor area of flaps was repaired with split-thickness skin graft from head or medium-thickness skin graft from thigh. The flap repair of wounds in various areas of the ankle and foot was recorded. The postoperative survivals of the flaps and skin grafts were observed after surgery. The postoperative appearance of flaps and walking function of patients were followed up. At the last follow-up, the foot and ankle function was evaluated and rated using the American Association of Foot and Ankle Surgeons Ankle Posterior Foot Scoring System. Results: Two wounds in toe area were repaired with reverse dorsal pedis flaps, 3 wounds in medial ankle area and 2 wounds in heel area were repaired with medial plantar flaps, 2 wounds in anterior plantar area combined with toe area were repaired with reverse medial plantar flaps, 2 wounds in anterior plantar area combined with toe area and 5 wounds in anterior plantar area were repaired with reverse medial pedis flaps, 1 wound in toe area was combined with proper plantar digital artery flap, 1 dorsal pedis wound and 1 lateral malleolus wound were repaired with lateral supramalleolar perforator flaps, and 1 lateral malleolus wound and 1 dorsal pedis wound were repaired with sural neurovascular flap. One flap had venous reflux disorder after surgery and survived after treatment, while the other flaps and skin grafts survived completely after surgery. During the follow-up of 6 to 24 months after operation, the appearance of the flaps was good, and the walking function of patients was normal. At the last follow-up, the functional score of foot and ankle was 76 to 95, which was evaluated as excellent in 11 cases and good in 5 cases. Conclusions: According to the condition of high-voltage electric burn in foot and ankle, early and thorough debridement, preoperative imaging examination to evaluate blood vessels of the affected limb, and selection of pedicled axial flap with reliable blood supply are good methods for wound repair and related functional reconstruction of high-voltage electric burn in foot and ankle.